Aristada

Aristada is part of the drug class:

• Other antipsychotics

Serious side effects have been reported with Aristada including the following:

• Stroke in elderly people (cardiovascular problems) that can lead to death.
• Neuroleptic malignant syndrome (NMS): Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms.
• Uncontrolled body movements (tardive dyskinesia): Aristada may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving Aristada. Tardive dyskinesia may also start after you stop receiving Aristada.
• Problems with your metabolism such as:
  • High blood sugar (hyperglycemia): Increases in blood sugar can happen in some people who take Aristada. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or a family history of diabetes), your healthcare provider should check your blood sugar before you start receiving Aristada and during your treatment. Call your healthcare provider if you have symptoms of high blood sugar while receiving Aristada such as feeling very thirsty, the need to urinate more than usual, feeling very hungry, feeling weak or tired, feeling sick to your stomach, confusion, and/or fruity breath
  • Increased fat levels (cholesterol and triglycerides) in your blood.
  • Weight gain. You and your healthcare provider should check your weight regularly.
• Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.
• Low white blood cell count
• Seizures (convulsions)
• Problems controlling your body temperature so that you feel too warm.
• Difficulty swallowing 
• Gambling urges and other uncontrollable (compulsive) behaviors such as an increased sex drive, spending money (compulsive shopping), binge eating or eating that you cannot control. If you or your family members notice any of these behaviors, speak with your health care provider. 

This medication may make you feel tired or have trouble with balance. This may lead to the risk of falls. 

Aristada may make you feel drowsy. Do not drive a car, operate machinery, or do other dangerous activities until you know how Aristada affects you.

Do not drink alcohol while you receive Aristada.

Do not become too hot or dehydrated while you receive Aristada.

• Do not exercise too much.
• In hot weather, stay inside in a cool place if possible.
• Stay out of the sun.
• Do not wear too much clothing or heavy clothing.
• Drink plenty of water

Do not take Aristada if you are allergic to Aristada or to any of its ingredients.

Dosage Forms & Strengths

tablet

• 2mg
• 5mg
• 10mg
• 15mg
• 20mg
• 30mg

oral disintegrating tablet

• 10mg
• 15mg

oral solution

• 1mg/mL

extended-release injectable IM suspension (Abilify Maintena)

• 300mg/vial or prefilled dual chamber syringe
• 400mg/vial or prefilled dual chamber syringe

extended-release injectable IM suspension (aripiprazole lauroxil [Aristada])

• 441mg/prefilled syringe (300 mg of aripiprazole)
• 662mg/prefilled syringe (450 mg of aripiprazole)
• 882mg/prefilled syringe (600 mg of aripiprazole)
• 1064mg/prefilled syringe (724 mg of aripiprazole)

Schizophrenia

PO

• 10-15 mg/day PO initially; may increase after 2 weeks at each dose strength; not to exceed 30 mg/day PO when administered as tablet formulation; efficacy not significantly greater above 15 mg/day

Abilify Maintena

• Patients who have never taken aripiprazole
  • 400 mg IM once monthly initially
  • Establish tolerability with aripiprazole PO prior to initiating treatment with Abilify Maintena; may take up to ~ 2 weeks to fully assess tolerability
  • Continue aripiprazole PO (10-20 mg/day) or other antipsychotics PO in patients with known aripiprazole tolerance for 14 consecutive days after initial injection
• Patients stabilized or aripiprazole tolerant
  • 400 mg IM once monthly
  • Administer monthly dose no sooner than 26 days after previous injection (also see Dosage Modifications)
  • Consider dose reduction to 300 mg/month if adverse reaction occurs
• See Administration

Aristada

• Establish tolerability with PO aripiprazole before initiating Aristada; may take up to 2 weeks to fully assess tolerability
• Base initial Aristada dose on current aripiprazole PO dose; coadminister aripiprazole PO for 21 consecutive days
• 10 mg/day PO: 441 mg IM once monthly
• 15 mg/day PO: 662 mg IM once monthly or 882 mg IM q6wk or 1064 mg IM q2mo
• ≥20 mg/day PO: 882 mg IM once monthly
• Adjust dose and dosing interval as needed; take into consideration the pharmacokinetics and prolonged-release characteristics of Aristada In the event of early dosing, Aristada should not be given earlier than 14 days after the previous injection
• See Administration

Bipolar Mania

PO

• Indicated for acute and maintenance treatment of manic or mixed episodes associated with bipolar I disorder, either as monotherapy or as adjunct to lithium or valproate
• Monotherapy: 15 mg/day PO initially; may be increased gradually; not to exceed 30 mg/day
• Adjunct to lithium or valproate: 10-15 mg/day PO initially; recommended daily dose is 15 mg/day; may be gradually increased; not to exceed 30 mg/day
• Continue stabilization dose for up to 6 weeks; treatment >6 weeks not studied

Abilify Maintena

• Patients who have never taken aripiprazole
  • 400 mg IM once monthly initially
  • Administer only by deep IM injection into deltoid or gluteal muscle by healthcare professional
  • Establish tolerability with aripiprazole PO prior to initiating treatment with Abilify Maintena; may take up to ~ 2 weeks to fully assess tolerability
  • Continue aripiprazole PO (10-20 mg/day) or other PO antipsychotics in patients with known aripiprazole tolerance for 14 consecutive days after initial injection
• Patients stabilized or aripiprazole tolerant
  • 400 mg IM once monthly
  • Administer monthly dose no sooner than 26 days after previous injection (also see Dosage Modifications)
  • Consider dose reduction to 300 mg/month if adverse reaction occurs

Major Depressive Disorder

2-5 mg/day PO initially; increased weekly PRN by ≤5 mg/day to dose range of 2-15 mg/day

Used adjunctively with other antidepressants

Dosage Modifications (Oral)

Coadministration with potent CYP2D6 or CYP3A4 inhibitors: Decrease dose by 50%

Coadministration with potent CYP2D6 inhibitor PLUS a potent CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%)

Coadministration with any CYP2D6 inhibitor PLUS any CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response

Poor CYP2D6 metabolizers: Decrease dose by 50% initially, and then adjust to a favorable clinical response

Poor CYP3A4 metabolizers: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response

Coadministration with potent CYP3A4 inducer: The usual dose should be doubled

Dosage Modifications (Abilify Maintena)

CYP2D6 poor metabolizers: 300 mg IM

CYP2D6 poor metabolizers taking concomitant CYP3A4 inhibitor: 200 mg IM

Patients taking 400 mg IM

• Strong CYP2D6 OR CYP3A4 inhibitors: 300 mg IM
• CYP2D6 AND CYP 3A4 inhibitors: 200 mg IM
• CYP3A4 inducers: Avoid use

Patients taking 300 mg IM

• Strong CYP2D6 OR CYP3A4 inhibitors: 200 mg IM
• CYP2D6 AND CYP 3A4 inhibitors: 160 mg IM
• CYP3A4 inducers: Avoid use

Missed doses

• 2nd or 3rd dose missed (>4 wk but <5 wk since last injection): Administer injection as soon as possible
• 2nd or 3rd dose missed (>5 wk since last injection): Restart concomitant oral aripiprazole for 14 days with next administered injection
• 4th or subsequent doses missed (>4 wk but <6 wk since last injection): Administer injection as soon as possible
• 4th or subsequent doses missed (>6 wk since last injection): Restart concomitant oral aripiprazole for 14 days with next administered injection

Dosage Modifications (Aristada)

No dosage changes if CYP450 modulators are added for <2 wk

Strong CYP3A4 inhibitor for >2 wk

• Reduce the dose to the next lower strength No dosage adjustment necessary in patients taking 441 mg, if tolerated
• Poor CYP2D6 metabolizers: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg; no dosage adjustment necessary in patients taking 441 mg, if tolerated

Strong CYP2D6 inhibitor for >2 wk

• Reduce the dose to the next lower strength
• No dosage adjustment necessary in patients taking 441 mg, if tolerated
• Poor CYP2D6 metabolizers: No dose adjustment required

Both strong CYP3A4 & CYP2D6 inhibitors for >2 wk

• Avoid use for patients taking 662 mg, 882 mg, or 1064 mg
• No dosage adjustment necessary in patients taking 441 mg, if tolerated

CYP3A4 inducers for >2 wk

• No dose adjustment for 662 mg, 882 mg, or 1064 mg
• Increase the 441 mg dose to 662 mg

Missed doses

• When a dose is missed, administer the next injection as soon as possible, unless the time has exceed 6-8 wk
• Supplemental PO doses should be the same as when the patient initiated Aristada
• See the following for recommendations for missed doses based on last injection dose
• Monthly 441 mg
  • ≤6 wk: No PO supplementation required
  • >6 wk and ≤7 wk: Supplement with 7 days of PO aripiprazole
  • >7 wk: Supplement with 21 days of PO aripiprazole
• Monthly 662 mg, monthly 882 mg, or 882 mg q6wk
  • ≤8 wk: No PO supplementation required
  • >8 wk and ≤12 wk: Supplement with 7 days of PO aripiprazole
  • >12 wk: Supplement with 21 days of PO aripiprazole
• 1064 mg q2mo
  • ≤10 wk: No PO supplementation required
  • >10 wk and ≤12 wk: Supplement with 7 days of PO aripiprazole
  • >12 wk: Supplement with 21 days of PO aripiprazole

Dosing Considerations

Dosing for oral disintegrating tablets is the same as for oral tablets

Dosage Forms & Strengths

tablet

• 2mg
• 5mg
• 10mg
• 15mg
• 20mg
• 30mg

tablet, orally disintegrating

• 10mg
• 15mg

oral solution

• 1mg/mL

Schizophrenia

13-17 years: 2 mg/day PO initially; increase to 5 mg/day after 2 days; may further increase to recommended dose of 10 mg/day after additional 2 days; subsequent doses may increase by 5 mg/day; maintenance: 10-30 mg/day

Bipolar Mania

Indicated for acute manic or mixed episodes, either as monotherapy or as adjunct to lithium or valproate

10-17 years: 2 mg/day PO initially; increased to 5 mg/day after 2 days; may further increase to recommended dosage of 10 mg/day after additional 2 days; subsequent doses may increase by 5 mg/day; maintenance: 10-30 mg/day

Autism

Indicated for irritability associated with autistic disorder

<6 years: Safety and efficacy not established

6-17 years: 2 mg/day PO initially; increase gradually at ≥1 week intervals to target dosage of 5 mg/day; may gradually be further increase PRN to 10 mg/day or higher; not to exceed 15 mg/day

Tourette Disorder

Indicated for treatment of Tourette disorder

<6 years: Safety and efficacy not established

6-18 years (<50 kg)

• Initiate at 2 mg/day PO with a target dose of 5 mg/day after 2 days
• The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics
• Dosage adjustments should occur gradually at intervals of no less than 1 week

6-18 years (≥50 kg)

• Initiate at 2 mg/day PO for 2 days, and then increase to 5 mg/day for 5 days, with a target dose of 10 mg/day on day 8
• The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics
• Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than 1 week

Dosage Modifications (Oral)

Coadministration with potent CYP2D6 or CYP3A4 inhibitors: Decrease dose by 50%

Coadministration with potent CYP2D6 inhibitor PLUS a potent CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%)

Coadministration with any CYP2D6 inhibitor PLUS any CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response

Poor CYP2D6 metabolizers: Decrease dose by 50% initially, and then adjust to a favorable clinical response

Poor CYP3A4 metabolizers: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response

Coadministration with potent CYP3A4 inducer: The usual dose should be doubled

Dosing Considerations

Dosing for oral disintegrating tablets is the same as for oral tablets

Aripiprazole lauroxil extended-release injection is used to treat schizophrenia (a mental disorder). It works in the brain to change how certain chemicals affect patients. Aripiprazole is an antipsychotic agent.

This medicine is available only with your doctor's prescription.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how Aristada affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Avoid drinking alcohol while taking this medicine.
• Talk with your doctor before you use other drugs and natural products that slow your actions.
• Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
• Low white blood cell counts have happened with drugs like this one. This may lead to a higher chance of getting an infection. Deadly infections have rarely happened. Tell your doctor if you have ever had a low white blood cell count. Call your doctor right away if you have signs of infection like fever, chills, or sore throat. Talk with your doctor.
• High blood sugar or diabetes, high cholesterol, and weight gain have happened with drugs like this one. These changes may raise the chance of heart and brain blood vessel disease. Talk with the doctor.
• Check your blood sugar as you have been told by your doctor.
• Dizziness, sleepiness, and feeling less stable may happen with Aristada. These may lead to falling. Broken bones or other health problems can happen from falling. Talk with the doctor.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Older adults with dementia taking drugs like this one have had a higher number of strokes. Sometimes these strokes have been deadly. This drug is not approved to treat mental problems caused by dementia. Talk with your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Aristada while you are pregnant.
• Taking this medicine in the third trimester of pregnancy may lead to muscle movements that cannot be controlled and withdrawal in the newborn. Talk with the doctor.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use Aristada as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a muscle.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Aristada is indicated for treatment of schizophrenia [see Clinical Studies (14)].

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aristada during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage. No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to 5 and 15 times, respectively, the maximum recommended human dose (MRHD) of 1064 mg based on body surface area (mg/m2). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data]. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization.

Data

Animal Data for Aripiprazole Lauroxil

Aripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.6 to 5 times the maximum recommended human dose (MRHD) of 1064 mg on mg/m2 basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 1 to 15 times the MRHD on mg/m2 basis. However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits [see Data below].

Animal Data for Aripiprazole

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately 1 to 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m2 basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight, and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m2 basis.

At 3 and 10 times the oral MRHD on mg/m2 basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on mg/m2 basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD on mg/m2 basis of aripiprazole during the period of organogenesis decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the oral MRHD based on AUC.

In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 times the oral MRHD on mg/m2 basis of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.

Lactation

Risk Summary

Aripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Aristada and any potential adverse effects on the breastfed infant from Aristada or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of Aristada in patients <18 years of age have not been evaluated.

Geriatric Use

Safety and effectiveness of Aristada in patients >65 years of age have not been evaluated.

CYP2D6 Poor Metabolizers

Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Hepatic and Renal Impairment

No dosage adjustment for Aristada is required based on a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see Clinical Pharmacology (12.3)].

Other Specific Populations

No dosage adjustment for Aristada is required on the basis of a patient's sex, race, or smoking status [see Clinical Pharmacology (12.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies have not been conducted with aripiprazole lauroxil.

Lifetime carcinogenicity studies with oral aripiprazole have been conducted in ICR mice and in Sprague-Dawley (SD) and F344 rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 times and 0.3 to 3 times the oral maximum recommended human dose [MRHD] of 30 mg/day based on mg/m2, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the oral MRHD based on mg/m2). Aripiprazole did not induce tumors in male mice or rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses which are 0.1 to 0.9 times human exposure at the oral MRHD based on AUC and 0.5 to 5 times the oral MRHD on mg/m2 basis. In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose which is 0.1 times human exposure at the oral MRHD based on AUC and 3 times the oral MRHD on mg/m2 basis; and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose which is 14 times human exposure at oral MRHD based on AUC and 19 times the oral MRHD on mg/m2 basis.

Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.

Mutagenesis

Aripiprazole lauroxil was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosome aberration assay in human peripheral blood lymphocytes.

Aripiprazole and its metabolite (2,3-DCPP) were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung (CHL) cells both in the presence and absence of metabolic activation. The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the oral in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans.

Impairment of Fertility

Animal Data for Aripiprazole Lauroxil

In a rat fertility study, aripiprazole lauroxil was administered intramuscularly. Males were treated with doses of 18, 49, or 144 mg /animal, which are approximately 0.4 to 3 times the maximum recommended human dose [MRHD] of 1064 mg on mg/m2 basis, on Days 1, 21, and 42 prior to and through mating; females were treated at these doses, which are approximately 0.6 to 5 times the MRHD on mg/m2 basis, once 14 days prior to mating.

In females, persistent diestrus was observed at all doses and the mean number of cycles was significantly decreased at the highest dose together with an increase in the copulatory interval (delay in mating). Additional changes at the high dose included slight increases in corpora lutea and pre-implantation loss, decline in mating, fertility, and fecundity indices in females and lower mating and fertility indices in males.

Animal Data for Aripiprazole

Female rats were treated with oral aripiprazole doses of 2, 6, and 20 mg/kg/day, which are 0.6 to 6 times the oral maximum recommended human dose [MRHD] of 30 mg/day on mg/m2 basis, from 2 weeks prior to mating through day 7 of gestation. Estrous cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was observed. Increased pre-implantation loss was found at 2 and 6 times the oral MRHD on mg/m2 basis and decreased fetal weight was noted at the highest dose which is 6 times the oral MRHD on mg/m2 basis.

Male rats were treated with oral aripiprazole doses of 20, 40, and 60 mg/kg/day, which are 6 to 19 times the oral MRHD on mg/m2 basis, from 9 weeks prior to and through mating. Disturbances in spermatogenesis at the highest dose and prostate atrophy at the mid and high doses were noted which are 13 and 19 times the oral MRHD on mg/m2 basis, but no impairment of fertility was observed.

Animal Toxicology and/or Pharmacology

Intramuscular administration of aripiprazole lauroxil to rats and dogs was associated with injection site tissue reactions at all doses in rats treated up to 6 months at doses of 15, 29, and 103 mg/animal (which are approximately 0.3 to 2 times and 0.5 to 3 times the maximum recommended human dose [MRHD] of 1064 mg on mg/m2 basis in males and females, respectively) and in dogs treated up to 9 months at doses of 147, 662, and 2058 mg/animal (which are approximately 0.5 to 6 times and 0.6 to 8 times the MRHD in males and females, respectively on mg/m2 basis). These injection site tissue reactions consisted of localized granulomatous inflammation and granuloma formation. Transiently impaired limb function and swelling occurred in dogs. The granulomas did not completely resolve 2 months following the last injection in the 6 month rat study and 4 months following the last injection in the 9 month dog study (the low dose groups were not examined for reversibility in these studies).

Orally administered aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg, which is 19 times the oral MRHD of 30 mg/day on mg/m2 basis, and in a 2-year carcinogenicity study at doses of 40 mg/kg and 60 mg/kg, which are 13 and 19 times the oral MRHD on mg/m2 basis and 7 to 14 times human exposure at the oral MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.

How Supplied

Aristada extended-release injectable suspension is available in strengths of 441 mg in 1.6 mL, 662 mg in 2.4 mL, 882 mg in 3.2 mL and 1064 mg in 3.9 mL. The kit contains a 5-mL pre-filled syringe containing Aristada sterile aqueous suspension and safety needles.

• The 441 mg strength kit (NDC 65757-401-03; light blue label) contains three safety needles; a 1-inch (25 mm) 21 gauge, a 1½-inch (38 mm) 20 gauge, and a 2-inch (50 mm) 20 gauge needle.
• The 662 mg strength kit (NDC 65757-402-03; green label) contains two safety needles; a 1½-inch (38 mm) 20 gauge and a 2-inch (50 mm) 20 gauge needle.
• The 882 mg strength kit (NDC 65757-403-03; burgundy label) contains two safety needles; a 1½-inch (38 mm) 20 gauge and a 2-inch (50 mm) 20 gauge needle.
• The 1064 mg strength kit (NDC 65757-404-03; dark blue label) contains two safety needles; a 1½-inch (38 mm) 20 gauge and a 2-inch (50 mm) 20 gauge needle.

Storage

Store at room temperature 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (between 59°F and 86°F).